White matter lesions (WMLs) and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that WML is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetes mellitus patients without insulin treatment. Based on brain magnetic resonance imaging findings, 55 type 2 diabetes mellitus patients were divided into 2 groups: a WML-positive group (59 +/- 5 years [mean +/- SD], n = 21) and a WML-negative group (58 +/- 6 years, n = 34). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. Baroreflex sensitivity was lower in the WML-positive group than in the WML-negative group (P < .01). Early and delayed (123)I-MIBG myocardial uptake values were lower (P < .005 and P < .001, respectively) and the percentage washout rate (WR) of (123)I-MIBG was higher (P < .0001) in the WML-positive group than in the WML-negative group. The fasting plasma glucose (P < .005) and insulin concentrations (P < .0001) and the homeostasis model assessment (HOMA) index values (P < .0001) were higher in the WML-positive group than in the WML-negative group. Multiple logistic regression analysis revealed that HOMA index and percentage WR of (123)I-MIBG were associated with WML patients. Our results suggested that WML was associated with depressed cardiovascular autonomic function and insulin resistance and that HOMA index and the percentage WR of (123)I-MIBG were independent associations for WML in Japanese patients with type 2 diabetes mellitus.